Molecular Signatures of a TLR4 Agonist-Adjuvanted HIV-1 Vaccine Candidate in Humans

Anderson, Jenna; McKay, Paul F.; Östensson, Malin; Persson, Josefine; Shattock, Robin J.; Harandi, Ali M.

doi:10.3389/fimmu.2018.00301

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…First, we performed a retrospective analysis that did not allow us to correct for influencing factors. In particular, inflammatory cytokines like IL6 ( Tanaka et al , 2014 ), but also ccf-mtDNA ( Grazioli and Pugin, 2018 ) have previously been reported to be increased in a number of inflammatory and cardiovascular diseases as well as in cancer. Thus, the specificity of the markers investigated in this study might be reduced if applied in clinical testing.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Borsche

König

Delcambre

et al. 2020

Brain

121

102

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There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Borsche

König

Delcambre

et al. 2020

Brain

121

102

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“…In recent years, systems vaccinology has emerged as an interdisciplinary approach that relies on high-throughput omics-based techniques to study vaccine-induced changes in the entire genome, set of transcripts, proteins, and metabolites in various tissues. A systems vaccinology approach has been used to elucidate immune responses to vaccines against yellow fever [102], influenza [103], malaria [104], smallpox [105] and HIV [106]. In addition, a systems vaccinology approach identified molecular and cellular immune signatures of a vaccine against Bordetella pertussis [107].…”

Section: New Approaches To Study Adjuvant Modes Of Actionmentioning

confidence: 99%

Selection of adjuvants for vaccines targeting specific pathogens

Sarkar

Garg

Hurk

2019

Expert Review of Vaccines

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Introduction: Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels. Different pathogens have distinct characteristics, which require the host to mount an appropriate immune response against them. Adjuvants can be selected to elicit a tailor-made immune response to specific pathogens based on their unique properties. Identification of biomarkers of adjuvanticity for several candidate vaccines using omics-based technologies can unravel the mechanism of action of modern and experimental adjuvants. Expert opinion: Adjuvant technology has been revolutionized over the last two decades. In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations. ARTICLE HISTORY

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“…A systems biology approach, integrating gene expression data with immunological results, has been used to study the human response to different vaccines ( 14 – 26 ). Systems biology is an interdisciplinary approach to analyze multiple data types related to complex biological interactions by using computational analysis and mathematical modeling.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics of the Vaccine Immune Response: Priming With Adjuvant Modulates Recall Innate Responses After Boosting

et al. 2018

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Transcriptomic profiling of the immune response induced by vaccine adjuvants is of critical importance for the rational design of vaccination strategies. In this study, transcriptomics was employed to profile the effect of the vaccine adjuvant used for priming on the immune response following re-exposure to the vaccine antigen alone. Mice were primed with the chimeric vaccine antigen H56 of Mycobacterium tuberculosis administered alone or with the CAF01 adjuvant and boosted with the antigen alone. mRNA sequencing was performed on blood samples collected 1, 2, and 7 days after priming and after boosting. Gene expression analysis at day 2 after priming showed that the CAF01 adjuvanted vaccine induced a stronger upregulation of the innate immunity modules compared with the unadjuvanted formulation. The immunostimulant effect of the CAF01 adjuvant, used in the primary immunization, was clearly seen after a booster immunization with a low dose of antigen alone. One day after boost, we observed a strong upregulation of multiple genes in blood of mice primed with H56 + CAF01 compared with mice primed with the H56 alone. In particular, blood transcription modules related to innate immune response, such as monocyte and neutrophil recruitment, activation of antigen-presenting cells, and interferon response were activated. Seven days after boost, differential expression of innate response genes faded while a moderate differential expression of T cell activation modules was appreciable. Indeed, immunological analysis showed a higher frequency of H56-specific CD4+ T cells and germinal center B cells in draining lymph nodes, a strong H56-specific humoral response and a higher frequency of antibody-secreting cells in spleen of mice primed with H56 + CAF01. Taken together, these data indicate that the adjuvant used for priming strongly reprograms the immune response that, upon boosting, results in a stronger recall innate response essential for shaping the downstream adaptive response.

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Molecular Signatures of a TLR4 Agonist-Adjuvanted HIV-1 Vaccine Candidate in Humans

Cited by 18 publications

References 38 publications

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Selection of adjuvants for vaccines targeting specific pathogens

Transcriptomics of the Vaccine Immune Response: Priming With Adjuvant Modulates Recall Innate Responses After Boosting

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